Can estrogen be causal factor of endometrial carcinoma?-Criteria to be the causal association, and whether previous publications satisfy these criteria
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There have been some evidences that estrogen might be responsible for endometrial carcinoma. The first evidence is the association between abnormally high level of endogenous estrogen and endometrial carcinoma. Namely women with estrogen-secreting ovarian tumor and those with poly-cysyic ovarian syndrome are at high risk of endometrial carcinoma. Also obese women are at high risk, because their plasma estrone is high level due to greater efficiency of conversion of androstenedione to estrone which is the strongest stimulator ofendometrial hyperplasia of alle strogens. The second evidence is that high dosage of exogenous estrogen in rabbit can produce endometrial carcinoma. On the other hand, much benefits of estrogen in terms of clinical trial have been established for the past three decades since synthetic estrogen has been available. According to the U. S. A. Department of Commerce figure, total amount of shipping of non-contraceptive estrogen of 1973 reached to 3.8 times as much as that of 1963. Based upon those basic knowledge, two epidemiological investigations of secular trend of incidence rate of endometrial carcinoma in U S. A. and four case-control studies which tried to clarify the association of estrogen to endometrial cancer have been published since 1974. Secular trend of endometrial carcinoma has not been clear, however, all of those case-control studies demonstrated the relationship between estrogen and endometrial carcinoma. Does estrogen have causal relationship with endometrial carcinoma? It is difficult to say. The problem of identifying causal relashionship in the more observational study is much more difficult. Nevertheless, it is of central importance. Detection of causal associations may indicate the key points at which a chain of disease production can be interrupted. On the other hand, it is important not to mislabel an association as causal if it is not, since that could initiate fruitless control efforts and deflect attention from moreprofitable approaches to prevention. Therefore, before any association is accepted as causal, all alternative explanations should be considered.Minagawa, J. who is one of the authors of this paper did have opportunity to study basic concept of epidemiology at The Johns Hopkins University, School of Hygiene and Public Health. In this paper, first of all, authors described the concept of causality and steps in the establishment of causal association. Most of these contents were cited from the lecture handout of epidemiology at The Johns Hopkins Univ ersity. Finally authors criticized the previously published thesises which showed the association of estrogens to endometrial carcinoma, and proposed the necessity of further epidemiological studies in order to elucidate much more whether estrogen can be the causal factor of endometrial carcinoma. The necessity and modification of further study was mentioned as below.1) When case-control studies are done, sample of cases or controls must be representative of all cases or controls. Therefore, selection of both cases and controls should be done carefully. Also the study designs have to be made so that various biases such as interviewer bias and recall bias can be eliminated as much as possible.2) In order to sutisfy the two of the criteria for causal association which are strength and consistency, epidemiological investigations have to be done in another places much more by using different method of selection of case and control.3) The most problem of case-control study for the judgement of causal association of estrogen to endometrial carcinoma is correct time sequence between the initiation of estrogen treatment and the incidence of endometrial carcinoma. Therefore, reasonable and practical latent period of endometrial carcinoma from incidence to diagnosable time must be hypothesized.4) These investigations must be done in conjunction with the study of secular trend of incidence rate of endometrial car
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